Toll-like receptor 9 and Systemic Lupus Erythromatosus: novel insights

Abstract

Toll-like receptor 9 (TLR9) is a pattern recognition receptor (PRR) which senses danger by recognizing DNA that is taken up into endosomal compartments of immune cells, most importantly of plasmacytoid dendritic cells. Activation of these cells by DNA leads to the generation of a strong, interferon-mediated Th1 response. However, also regulatory functions for TLR9 activation have been reported. Novel evidence suggests that the distinction between self- and foreign DNA by TLR9 is much more limited than previously thought, and depends on the localization of the antigen rather than sequence motifs. The endolysosomal localization is also required to prime TLR9 for activation by pH dependent proteolytic processing of its antigen binding domain. Therefore the localization of TLR9 is carefully controlled by a transport mechanism which contains the newly identified protein UNC93B. The lack of specificity in DNA sensing emphasizes the risk TLR9 poses in respect to developing autoimmune diseases. Indeed, TLR9 polymorphisms have been correlated with multiple autoimmune diseases. The best studied TLR9-related autoimmune disease thus far is Systemic Lupus Erythromatosus (SLE). In SLE, TLR9 seems to have activating, but also suppressive roles. HMGB1, which was recently identified as a stimulator of CpG-mediated TLR9 activation, may also play a role in SLE. Stable synthetic oligodeoxiribonucleotides with different activating and suppressing capacities provide a spectrum of potential drugs and adjuvants for future therapeutic strategies.